The Unique Features and Collateral Immune Effects of mRNA-Based COVID-19 Vaccines: Potential Plausible Causes of Adverse Events and Complications

The lipid nanoparticle (LNP)-enclosed mRNA-containing COVID-19 vaccines were used successfully to vaccinate billions of people during the COVID-19 pandemic. However, as with all medicines, Comirnaty and Spikevax can also cause adverse events (AEs) and complications. Although such events occur in less than 0.5% of vaccinated individuals, the huge scale of global vaccination means that the number of "vaccine injuries" could reach millions worldwide. These AEs have a uniquely broad spectrum affecting multiple organs, with most cases being associated with inflammatory and autoimmune processes. Yet, the clinical significance of AEs is debated, and their cellular and molecular mechanisms are poorly understood. The present review surveys the distinctive structural and functional features of these vaccines linking them to secondary immune effects causing unusual AEs/complications. The discussed unique mRNA-LNP properties include the ribosomal synthesis of the spike protein (SP) fundamentally transforming antigen processing and presentation; the multiple chemical modifications of the mRNA, increasing its stability and translation efficacy; toxicity of the SP casing multiorgan damage; immune stimulation and mRNA transfection by LNP; reduced stability of vaccine nanoparticles in water; immune reactivity and immunogenicity of PEG on the LNP surface; stabilization of the SP by enrichment with proline; and contaminations of the vaccine with plasmid DNA and inorganic elements or complexes. The considered collateral immune effects that may theoretically underlie the AEs are: diversification of the processing and presentation of the SP, innate immune activation, T-cell and antibody-mediated cytotoxicities, dissemination of virus/vaccine hybrid exosomes, somatic hypermutation, reverse transcription, insertion mutagenesis and frameshift mutation. Highlighting these potential processes may help update the risk/benefit ratio of the currently used formulations and make future products of the mRNA-LNP technology platform safer.